Most humans (>80%) that develop Adult T-cell LymphomalLeukemia (ATL) due to HTLV-1 infection develop humoral hypercalcemia of malignancy (HHM), which is an important cause of morbidity and mortality in affected patients. It was reported that the Tax transforming protein of HTLV-1 was able to stimulate parathyroid hormone-related protein (PTHrP) expression in vitro, and that this may be the mechanism for overexpression of PTHrP in ATE However, we and others have shown that Tax is not expressed in ATE Therefore, there must be other important mechanisms to induce PTHrP expression. We have recently developed a new SCID/beige mouse model of human ATL and have used the model to characterize the pathogenesis of hypercalcemia in vivo. There was very high PTHrP expression (using PTHrP promoters 2 and 3) and no Tax expression. Recent data from our laboratory has demonstrated that PTHrP mRNA expression in human ATL is dependent on NFkappaB, Ets, and STAr transcription factors and T-cell receptor activation signal transduction pathways. VVe hypothesize that PTHrP is important in transformation of human T-cells by HTLV-1, growth of ATL, and central to the pathogenesis of HHM in ATL patients. PTHrP expression will be dependent on Tax during T-cell transformation and independent of Tax in ATE PTHrP will act cooperatively with cytokines (IL-1, TNFalpha, and MIP-1alpha) to induce HHM. There are three specific aims to this proposal: 1) Investigate the role of PTHrP in human T-cell proliferation, apoptosis, and transformation by HTLV-1 infection of human T-cells in vitro and rabbits in vivo, 2) Investigate the regulation of PTHrP mRNA expression & stability and secretion in human ATL, mouse models of human ATL, and T-cell lymphoma in Tax-transgenic mice, and 3) investigate the roles of PTHrP and cytokines in the development and treatment of HHM in mouse models of human ATL, Successful complete of the three aims will be dependent on data, animal models (HTLV-1 infection in rabbits & Tax-transgenic mice), and scientific collaboration provided by projects 1, 2, 3, & 5, and imaging, animal model, and data analysis support from Cores A, B, & C. Our overall goal for the experiments is to understand the regulation and roles of PTHrP in the development of T-cell malignancy and cancer-associated hypercalcemia in humans with ATL.